Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell
RNA sequencing of human diabetic
wounds, we identified increased JMJD3 in diabetic
wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated
inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that
IL-6, a
cytokine increased in diabetic
wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic
wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in
wound macrophages via an H3K27me3 mechanism. Interestingly,
RNA sequencing of
wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3f/fLyz2Cre+) identified that the
STING gene (Tmem173) is regulated by JMJD3 in
wound macrophages.
STING limits inflammatory
cytokine production by
wound macrophages during healing. However, in diabetic mice, its role changes to limit
wound repair and enhance
inflammation. This finding is important since
STING is associated with chronic
inflammation, and we found
STING to be elevated in human and murine diabetic
wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic
wounds significantly improves diabetic
wound repair by decreasing inflammatory
cytokines and
STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic
wounds.